The overal aim of my project is the study of the interplay between the insulin-like growth factor (IGF) axis and the regulation of insulin secretion and glucose utilization. I am studying these relationships using a combined clinical and molecular approach which includes carefully designed GCRC studies of insulin secretion and fasting in patients with diabetes mellitus and hypoglycemic disorders and in-vitro models of insulin and IGF axis parameters: Specific Aim 1a: IGF-I in Hyperinsulinism Hypothesizing that IGF-I would ameliorate hypoglycemia due to hyperinsulinism by reducing insulin secretion, we enrolled a total of eight patients in an open label trial of recombinant human IGF-I. The majority of these children had known defects in the beta cell sulfonylurea receptor. All had suboptimal blood glucose levels, and patients served as their own controls. Subjects underwent 24 hour blood glucose monitoring under their home regimens followed by a supervised fasting study. The controlled fast was terminated when the child became hypoglycemic (blood glucose < 50 mg/dl) or developed symptoms consistent with hypoglycemia. The fast was repeated under rhIGF-I at 40 mcg/kg/dose SQ 2 12 hours. We demonstrated that rhIGF-I significantly lowered baseline serum C-peptide levels (at the start of fasting) by 48% (p<0.008) and baseline insulin levels by 60% (p<0.02)(1). rhIGF-I suppression of insulin and C-peptide persisted throughput the fast. Our data suggests that the IGF inhibition of insulin secretion occurs by a mechanism independent of the sulfonylurea receptor. The most likely alternative pathway is via the Type I IGF Receptor, which we have previously demonstrated in beta cells. Studies of Insulin-growth factor-I effects in beta cell models are underway. Specific Aim 1b IGF-I in the Treatment of Diabetes is temporarily on hold because of the lack of availability of rhIGF-I for investigational use. RhIGF-I had been supplied by Pharmacia for Specific Aim #1a, but the drug has since been discontinued by the manufacturer. Specific Aim #2 IGFBP-1 in Fasting and Diabetic Ketoacidosis We are studying the relationships between insulin, secretion, insulin-like growth factor-I, and Insulin-like growth factor binding protein-1 during states of fasting and diabetic ketoacidosis. Recruitment is ongoing. We have determined that IGFBP-1 levels are strongly related to serum cortisol levels during fasting, and the results have been published (2). Specific Aim #3A IGFBP-1 in the Diagnosis of Type 2 Diabetes We are studying IGFBP-1 levels in newly diagnosed diabetics as a marker of insulin secretion/sensitivity, in an attempt to create a diagnostic model to distinguish children with Type 1 from Type 2 diabetes mellitus. We are also studying fasting levels of IGFBP-1, together with insulin, and C-peptide as a part of outpatient follow-up of patients with Type II Diabetes. Recruitment is Ongoing. Specific Aim 3B IGFBP-1 In Neonatal Hypoglycemia We are studying infants with neonatal hyperglycemia to determine whether IGFBP-1 levels are an effective marker of hypoglycemia due to insulin excess. Recruitment will begin shortly.